Efficacy of the Novel Antidepressant Agomelatine on the Circadian Rest-Activity Cycle and Depressive and Anxiety Symptoms in Patients With Major Depressive.

Efficacy of the Novel Antidepressant Agomelatine on the Circadian Rest-Activity Cycle and Depressive and Anxiety Symptoms in Patients With Major Depressive Disorder:

A Randomized, Double-Blind Comparison With Sertaline

Mohammed Almoslem Pharm.D. CandidateKing Saud University & King Khalid University HospitalPsychiatric Rotation

Supervised by: Dr. Solafa Fatani Ms.c.

Journal Club Presentation

Outline

• Introduction • Relevance • Validity – Method– Statistical analysis

• Results • Strengths • Limitations • Conclusion • Final Message

• Title: – Efficacy of the Novel Antidepressant Agomelatine on the Circadian Rest-

Activity Cycle and Depressive and Anxiety Symptoms in Patients With Major Depressive Disorder: A Randomized, Double-Blind Comparison With Sertaline

• Journal: – The journal of clinical psychiatry

• Authors: – Kasper S, Hajak G, et al

• Study Design: – International, Randomized, double-blind, parallel-group

• Funding: – This study was sponsored by Servier (Courbevoie,France)

Introduction

Paper Information

• 16.2% of the population had a history of Major Depressive Disorder• More than 6.6% had episodes in one year.• MDD medication are classified as following:

– Monoamine Oxidase Inhibitors (MAOIs)• Hypertensive crisis, food interaction

– Tricyclic Antidepressants (TCAs)• Anticholenergic, orthostatic hypotension

– Selective Serotonin Reuptake inhibitors (SSRIs)• Wait gain, sexual dysfunction

– Serotonin-Norepinephrine Reuptake inhibitors (SNRIs)• Hypertension, liver toxicity

– Atypical antidepressants• Liver toxicity, psychosis

Dipiro, et al, pharmacotherapy a pathophysiological approach 7th edition

Introduction

Major Depressive Disorder (MDD)

Introduction

Agomelatine

• The first melatonergic antidepressant • Potent MT1/ MT2 receptor agonist• 5-HT2C receptor antagonist• Resynchronize altered circadian rhythm in depressive or healthy

individuals

• Endogenous physiological processes that regulates the cycle of 24 hour in living beings

• Circa: around or approximately • Diem or dies: day

Introduction

Circadian Rhythm

Introduction

Circadian Rhythm

• A useful proved method that measures the circadian rest and activity patterns

• Indirectly measurement of sleep and characterize 24-hour sleep-wake cycle

Introduction

Actigraphy

Introduction

Objective• Primary:Demonstrate that agomelatine (25–50 mg/d) improved the circadian

rest-activity cycle faster than sertraline in MDD outpatients

• Secondary:Assess the efficacy and tolerability of agomelatine on depressive and

anxiety symptoms compared with sertraline through its effect on sleep efficacy and latency

• Sleep disruption is a major symptom in depression, with over 90% of patients suffering from sleep complaints

• There is a close link between the regulation of sleep and circadian rhythms and the regulation of mood

Thase ME. Antidepressant treatment of the depressed patient with insomnia. J Clin Psychiatry. 1999;60(suppl 17):28–31, discussion 46–48. PubMedBirchler-Pedross A, Schroder CM, Munch M, et al. Subjective well-being is modulated by circadian phase, sleep pressure, age and gender. J Biol Rhythms. 2009;24(3):232–242. PubMed doi:10.17/07487304093546

Boivin DB, Czeisler CA, Dijk DJ, et al. Complex interaction of the sleepwake cycle and circadian phase modulates mood in healthy subjects. Arch Gen Psychiatry. 997;54(2):145–152

Relevance

Validity

Method• Hypothesis:The nocturnal disturbances of sleep onset, continuity, and/or

awakening, together with daytime retardation and napping, lead to a reduced Relative Amplitude, and that improvement of the former leads to increase of the latter.

• Randomization:– International, double-blind, parallel-group – Conducted from 2005-2006 in 37 centers in 6 European

countries • (France, Germany, Austria, Spain, Italy, and Poland)

Validity cont.

Method

• Allocation:– Inclusion criteria

• MDD diagnosed male and female outpatients aged 18 to 60 years• Confirmed by the Mini-International Neuropsychiatric Interview• Match the items standard of Hamilton Depression Rating Scale

(HDRS)• Single or recurrent episodes that match the criteria of DSM-IV-TR• The current episode had already lasted at least 4 weeks• Should not have seasonal pattern, psychotic features, or

catatonic symptoms and were not postpartum

Validity cont.

Method

• Allocation:– Exclusion criteria

• High risk of suicide or a previous suicide attempt within 6 months• Bipolar disorder• Anxiety symptoms• Drug abuse or dependency within the past 12 months• Previous antidepressants resistance• ECT therapy or formal psychotherapy within 3 months• Light-therapy started within 2 weeks• Positive screened for sleep disorders• Neurologic disorders• Obesity with functional impairment• Serious or not stabilized organic• Other antidepressants were prohibited for washout

Validity cont.

Method

ECT: electroconvulsive therapy

Validity cont.

Method• Allocation:

– Disposition of included patients:

Validity cont.

Method• Attrition

– 6 patients were not included inthe Full Analysis Set• 4 in agomelatine group• 2 in sertaline group

Due to absence of treatmentintake or no postbaseline efficacy assessment

– The Actigraphy Analysis Setcomprised only (73%) 233 pts.• 117 (76%) of the agomelatine• 116 (73%) of sertaline

Validity cont.

Method• Demographic

characteristics:

• Blindness and concealment– Blindness:

• All patients took orally 2 tablets once a day in the evening• Daily dosage irrespective to the treatment• Same appearance and the taste of the study treatment during

the study period for all patients• The packaging and the labeling were identical• Statistical analysis group ??????

– Concealment:• Three hundred seventy-two patients were screened, and 313

patients were randomly assigned to receive– Agomelatine (154 patients)– Sertaline (159 patients).

• The concealment was NOT mentioned in the study.

Validity cont.

Method

• Intention to treat:– The actigraphy analysis set (AAS), defined, for objective sleep

criteria analyses, as all randomized patients who took at least 1 dose of study treatment and had 1 reliable baseline value and at least 1 reliable postbaseline value for the RA

– The full analysis set (FAS), defined, for other efficacy criteria analyses, as all randomized patients who took at least 1 dose of study treatment and had at least 1 postbaseline efficacy assessment (other than actigraphic) over the 6-week treatment period.

Validity cont.

Method

• Actigraphy Analysis Set (AAS)– For sleep data analysis

• Mixed-effects model with repeated measures (MMRM)• Full Analysis Set (FAS)

– For depression data analysis• Hamilton Depression Rating Scale (HDRS)

– 2-way analysis of covariance– 2-sided Student t test– X2 test– Post hoc analysis

• Clinical Global Impressions scale (CGI)• Leeds Sleep Evaluation Questionnaire (LSEQ)

– For anxiety data analysis• Hamilton Anxiety Rating Scale (HARS)

– 1-way analysis of covariance– Post hoc analysis

Validity cont.

Statistical Analysis

Results cont.

Efficacy on the Circadian Rest-Activity Cycle

Mean ± SD P-value

Mean RA 1st week .010

AAS evolution of the mean RA over time .023

Mean RA 2nd week .148

Mean RA 3rd week .521

Mean M10

Agomelatine(386.6 ± 6914.9)

.006Sertraline

( - 430.5 ± 5934.2)

Mean L5

Agomelatine(-120.8 ± 1302.8)

.121Sertraline

( - 366.8 ± 1367.1)

RA: relative amplitude. M10: activity of maximum 10 hours. L5: activity of minimum 5 hours.

• Baseline and Difference in Sleep Efficiency (A) and Sleep Latency (B) Between Treatment Groups Over Each Postbaseline 7-Day Period in the Actigraphy Analysis Set

Results cont.

Efficacy on Actigraphy-Derived Sleep Parameters

• Change in LSEQ Getting to Sleep (A) and Quality of Sleep (B) Scores (mm) From Baseline to Last Postbaseline Value Over the Week 0–Week 6 Period in the Full Analysis Set

a: P value, treatment effect: 2-sided Student t test for independent samples.Abbreviation: LSEQ = Leeds Sleep Evaluation Questionnaire

Results cont.

Efficacy on Subjective Sleep

• Change in HDRS Total Score From Baseline to Last Postbaseline Assessment Over the 6-Week Period (week 0–week 6) in the Full Analysis Set

a: Two-way analysis of covariance with treatment and center (as random effect) as factors and week 0 HDRS total score as covariate.b: Estimate (standard error) of the difference between adjusted treatment group means: sertraline minus agomelatine.c: 95% CI of the difference.d: P value of treatment effect.Abbreviation: HDRS = Hamilton Depression Rating Scale.

Results cont.

Efficacy on Depressive symptoms

Results cont.

Clinical Global Impressions scale• The data will be provided later on

Results cont.

Efficacy on Anxiety Symptoms• The data will be provided later on

• Most Frequently Reported Emergent Adverse Events (≥ 5.0% of patients in any treatment group), Expressed as Percentage of Affected Patients Among Exposed Patients During the Double-Blind Treatment Period in the Safety Set

Results cont.

The safety data were not statistically analyzed and only emergent adverseevents (EAEs) that reported by less than 5% of the patients were NOT provided

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Study Strengths

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Study Limitations

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Study Conclusion

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Final Message

Thank You …